The present disclosure generally relates to a new process for the preparation of high purity 5-nitro-isophthalamide compounds, which are useful as intermediates for the preparation of imaging agents, such as iodinated x-ray contrast imaging agents like ioversol, iohexyl and iopamidol.
5-nitro-isophthalamide compounds (also generally referred to herein as “diamides”) of general formula (2) below, where R is a C1 to C18 straight or branched chain hydrocarbyl or substituted hydrocarbyl moiety, are useful synthetic intermediates for the preparation of organoiodine compounds, such as ioversol, iohexyl and iopamidol.
Compounds of formula (2) are typically prepared by contacting a 5-nitro-isophthalate compound of formula (1) below (i.e., a “diester”), where R1 and R2 are independently a C1 to C18 straight or branched chain hydrocarbyl or substituted hydrocarbyl moiety, with a stoichiometric excess of at least 10% of a primary amine of formula RNH2 in a suitable solvent. (See, e.g., U.S. Pat. No. 7,244,864, the entire contents of which are incorporated herein by reference for all relevant and consistent purposes.)

Typically, a ratio of primary amine to diester of greater than 2.2:1, on a molar equivalent basis, is required to achieve a commercially acceptable yield of diamide formula (2). Problematically, diamide reaction mixtures prepared by such a process typically contain relatively high amounts of unreacted diester and primary amine, as well as substantial quantities of reaction impurities, that must be removed in subsequent purification steps to generate a diamide of suitable purity. Impurities include the acid amide of formula (3), and amide esters of formulae (4) and (5) below:

In contrast to the process as outlined above, U.S. Pat. No. 6,441,235 B1 (to Parady, et al.) discloses an alternative process for the preparation of diamides of formula (2). In the this process, one molar equivalent of diester of formula (1) is reacted with 2.1 molar equivalents of a primary amine in a solvent system comprising a basic catalyst, at a temperature of between 65° C. and 150° C. and at the boiling point (i.e., reflux temperature) of the solvent system. Problematically, the Parady et al. process is run at relatively dilute concentrations, utilizes a significant stoichiometric excess of primary amine, and high reaction temperature, and thus generates a reaction product mixture having high levels of the acid amide and amide ester impurities.
Accordingly, a need continues to exist for an improved method for preparing 5-nitro-isophthalamide compounds in high yield, purity and throughput.